There is convincing evidence from family, adoption and twin research for the importance of familial factors in the development of alcohol dependence. Laboratory studies have been conducted with offspring of alcoholics who have not yet themselves developed the disorder in an effort to identify markers associated with the future development of alcoholism. Differences in alcohol sensitivity have been found as a fundtion of familial alcoholism history. More recently, our and others' research has examined the generalization to other drug classes of this differential sensitivity associated with familial alcoholism. The proposed research project will examine the role of a family history of alcoholism in modulating responses to marijuana, employing both controlled dosing and self-administration procedures. Epidemiological evidence from our own research and others' has shown that family history positive youth use marijuana at a greater frequency, report an earlier age of first use of marijuana, and report more problems as a result of drug use than family history negative youth. Subjects include males and females aged 18-25 with a high density of familial alcoholism and matched comparison groups with no history of familial alcoholism. Four broad response dimensions are measured in laboratory experimental sessions comprised of periodic testing batteries to establish baseline levels, and to asses responses to drug ingestion. We are currently examining the role of familial alcoholism as a determinant of the dose-effects of smoked marijuana (0, 2.5, and 4% THC); ethanol (1 g/kg) also is administered to allow an explicit comparison of the magnitude of family history group differences in response to these two drugs. Four broad dimensions of responses are studied: physiological, psychomotor, subjective, and behavioral. Of particular interest are smoking topography measures such as puff volume, duration and patterning, as well as neuroendocrine measures including ACTH, beta-endorphins, prolactin, and growth hormone. Additional measures that have been shown in our previous research to differentiate the family history groups are self- reports of mood, euphoria and hangover, the autonomic measures of heart rate and skin conductance, as well as psychomotor performance measures such as digit symbol substitution test, and other reaction time and cognitive tasks. Data will be analyzed as a function of both family history and gender factors. If we find differential sensitivity to, and/or differential rates of self-administration of marijuana, this suggests that family-history positive youth may not only be at increased risk for future development of alcoholism, but also at increased risk for the development of other psychoactive substance abuse disorders.